Chianese, Rosanna

Colledge, Bill

Fasano, Silvia

Meccariello, Rosaria

Colledge, William H

Apollo (Cambridge)

EDITORIALpublished: 03 December 2018doi: 10.3389/fendo.2018.00727Frontiers in Endocrinology | www.frontiersin.org 1 December 2018 | Volume 9 | Article 727Edited by:Cunming Duan,University of Michigan, United StatesReviewed by:Chunyang Zhang,Harvard Medical School,United States*Correspondence:Rosaria Meccariellorosaria.meccariello@uniparthenope.itSpecialty section:This article was submitted toExperimental Endocrinology,a section of the journalFrontiers in EndocrinologyReceived: 04 October 2018Accepted: 16 November 2018Published: 03 December 2018Citation:Chianese R, Colledge WH, Fasano Sand Meccariello R (2018) Editorial: TheMultiple Facets of Kisspeptin Activityin Biological Systems.Front. Endocrinol. 9:727.doi: 10.3389/fendo.2018.00727Editorial: The Multiple Facets ofKisspeptin Activity in BiologicalSystemsRosanna Chianese 1, William H. Colledge 2, Silvia Fasano 1 and Rosaria Meccariello 3*1Department of Experimental Medicine, University of Campania L. Vanvitelli, Naples, Italy, 2Department of Physiology,Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom, 3Department of MovementSciences and Wellbeing, Parthenope University of Naples, Naples, ItalyKeywords: Kisspeptin, cancer, reproduction, puberty, metabolism, comparative genomics, non-hypothalamicactivitiesEditorial on the Research TopicThe Multiple Facets of Kisspeptin Activity in Biological SystemsIn 1996, as part of a screen for anti-metastatic genes, a novel gene termed Kiss1 was found to beexpressed in non-metastatic melanoma cell lines (1). Its 54 amino-acid product, Kisspeptin-54(Kp-54), was originally called metastin for its ability to inhibit cancer metastasis through theactivation of a G protein coupled receptor, previously known as GPR54, and currently renamedthe Kisspeptin receptor (KISS1R) (2, 3).Kp-54 is the longest cleavage product of the Kisspeptin precursor protein, but there are shorteractive peptides [i.e., Kp-14, Kp-13, and Kp-10], all capable of binding to KISS1R (3). Since the tissuedistribution of KISS1R was very similar in mammalian and non-mammalian vertebrates, especiallyin the brain, it was suggested that kisspeptins not only acted as metastasis suppressors, but also werea new family of evolutionarily conserved biological modulators (4).In both rodents and humans, genetic ablation or inactivating mutations of the Kiss1/Kiss1Rgenes cause lack of sexual maturation and hypogonadotropic hypogonadism. Conversely,functionally activating mutations of Kiss1/Kiss1R genes cause precocious puberty (5, 6). Thus,most studies have focused on the involvement of Kisspeptin activity in the central controlof reproduction, through the regulation of hypothalamic Gonadotropin Releasing Hormone(GnRH) neurons, which depends on the hormonal milieu, energy homeostasis, and environmentalfactors (7).The twelve articles in this Research Topic provide a comprehensive insight into the widerphysiological actions of Kisspeptin beyond the reproductive system including cancer, metabolismand neuroscience and also highlight the role of Kisspeptins in non-mammalian species.Two mini reviews and a review article focus on Kisspeptin and cancer suggesting that theKisspeptin system is a potential therapeutic agent and/or a prognostic marker for some types ofcancer. Ciaramella et al. summarize the latest data concerning the role of Kisspeptin signaling inthe suppression of metastasis in cancer, whereas Fratangelo et al. point out additional Kisspeptinactivity in tumors especially those with drug resistance. Indeed, new evidence reveals thatKisspeptins can exhibit dual roles in cancer either acting as suppressors of tumorigenesis andmetastasis in many cancers or as enhancers in others. In this respect, Guzman et al. highlight theimportance of studying cancer in context with attention toward the micro-environment and thesteroid receptor status of the cancer cell.Moving toward the hypothalamic activity of Kisspeptin, the review submitted by Terasawaet al. concerns the contribution of Kisspeptin and Neurokinin B (NKB) signaling in thepubertal increase in GnRH release in female non-human primates. Reciprocal signaling pathwaysbetween Kisspeptin and NKB neurons are indispensable to facilitate the pubertal increase inChianese et al. Multiple Facets of Kisspeptin ActivityGnRH necessary for the reproductive function in females. Incontrast, Kisspeptin as the gatekeeper of reproduction andsex maturation in non-mammalian vertebrates which exhibitmore complex GnRH and Kisspeptin systems with multipleforms of ligands and receptors (4, 8), is not as clear as inmammals. In this respect, Ohga et al. summarize Kisspeptinstudies in the teleost chub mackerel and elucidate the possiblerole in fish reproduction and gonadal development. Furthermore,the research article by Pasquier et al. concerns the cloning,sequencing, and differential expression of Kiss1 and Kiss2 in boththe brain and peripheral tissues from the European eel. A dualinhibitory effect of homologous Kisspeptins on the expressionrate of both pituitary LHβ and GnRH receptor2 has been alsoreported.A large body of data has established that KISS1 neurons arecapable of integrating information about the hormonal milieu,environmental factors, stress signals, metabolism and energybalance, and conveying this information to GnRH secretingneurons. Consequently, the focus on the central role of theKisspeptins has led to neglecting their possible activities inperipheral tissues. Increasing data reveal that Kisspeptins andKISS1R have a wider expression and possibly a broader spectrumof action in several peripheral tissues such as the gonads, adiposetissue, and liver with direct consequences on gamete quality andfertility rate, pregnancy, energy homeostasis, and body weightcontrol (9).These points have been fully assessed in this Research Topic.The intricate neuronal networks and the related environmentalfactors capable to modulate the reproductive axis via KISS1neurons have been summarized by Yeo and Colledge. Theseauthors also describe the main experimental approaches forinvestigating functional inputs to KISS1 neurons in the arcuatenucleus. Furthermore, the regulation of the hypothalamicKisspeptin-KISS1R signaling by metabolic cues and in othersituations of energy imbalance like diabetes and obesity hasbeen extensively analyzed by Wahab et al. The direct impactof Kisspeptin on peripheral metabolic tissues has only recentlybeen recognized and emerging data from animal models andclinical studies have been summarized in two review articles. Thefirst one, by Wolfe and Hussain, focuses on the endocrine roleof Kisspeptin in the central and local regulation of metabolicfunctions; the participation of liver-derived Kisspeptin in islethormone cross-talk and the peripheral sources of circulatingKisspeptin (i.e., placenta and adipose tissues). The second oneby Dudek et al. focuses on the local activity of Kisspeptin inperipheral organs such as the pancreas, liver and adipose tissueand the dysregulation of the Kisspeptin system in metabolicdiseases (e.g., obesity and diabetes) in humans, situations that areoften linked to reproductive disorders and infertility.Finally, this Research Topic closes with a focus on extra-hypothalamic activity of Kisspeptin in both mammalian andnon-mammalian vertebrates. In particular, the review by Ogawaand Parhar provides a survey of Kisspeptin signaling within thehabenula of fish, the brain area involved in the neuromodulatoryprocesses of emotional and goal-directed behaviors. Lastly,Stephens and Kauffman summarize what is currently knownabout the regulation, development, neural projections, andpotential functions of Kisspeptin neurons located within themedial amygdala and discuss both the related signaling and thepossible implication in many diverse functions and behavioralprocesses.Taken together, this Research Topic fills several gapsin Kisspeptin knowledge and provides exciting tools forfuture directions devoted to the use of Kisspeptin asprognostic/diagnostic biomarkers and therapeutic targetfor the treatment of cancer and other human diseases likeinfertility in both sexes and metabolic disorders.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.FUNDINGThis work was funded by Parthenope University of Naples to RM.REFERENCES1. Lee J, Miele M, Hicks D, Phillips K, Trent J, Weissman B, et al. KiSS-1, a novelhuman malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst.(1996) 88:1731–7. doi: 10.1093/jnci/88.23.17312. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al.Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature (2001) 411:613–7. doi: 10.1038/350791353. Lee DK, Nguyen T, O’neill GP, Cheng R, Liu Y, Howard AD, et al. Discoveryof a receptor related to the galanin receptors. FEBS Lett. (1999) 446:103–7.doi: 10.1016/S0014-5793(99)00009-54. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. EndocrRev. (2009) 30:713–43. doi: 10.1210/er.2009-00055. Seminara S, Messager S, Chatzidaki E, Thresher R, Acierno J, Shagoury J, et al.The GPR54 gene as a regulator of puberty. N Engl J Med. (2003) 349:1614–27.doi: 10.1056/NEJMoa0353226. de Roux N, Genin E, Carel J, Matsuda F, Chaussain J, Milgrom E.Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.Proc Natl Acad Sci USA. (2003) 100:10972–6.doi: 10.1073/pnas.18343991007. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins andreproduction: physiological roles and regulatory mechanisms. Physiol Rev.(2012) 92:1235–316. doi: 10.1152/physrev.00037.20108. Pierantoni R, Cobellis G, Meccariello R, Fasano S. Evolutionary aspects ofcellular communication in the vertebrate hypothalamo-hypophysio-gonadalaxis. Int Rev Cytol. (2002) 218:69–141. doi: 10.1016/S0074-7696(02)18012-09. De Bond JA, Smith JT. Kisspeptin and energy balance in reproduction.Reproduction (2014) 147:53–63. doi: 10.1530/REP-13-0509Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2018 Chianese, Colledge, Fasano andMeccariello. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Endocrinology | www.frontiersin.org 2 December 2018 | Volume 9 | Article 727

Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems.

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Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems.

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